Plasma natriuretic peptide levels are markedly elevated in individuals with left ventricular hypertrophy (LVH), one of the key precursors of diastolic heart failure (DHF). However, experiments using gene knockout mice indicate that natriuretic peptide deficiency (not excess) leads to progressive LVH. This apparent paradox is explained by the important counter-regulatory function of the natriuretic peptides, which are secreted in response to atrial and ventricular wall stress. In experimental models, natriuretic peptides have two paracrine effects on the heart: enhanced lusitropy and inhibition of myocyte hypertrophy and fibrosis. It is hypothesized that deficiency of natriuretic peptides contributes to the development of LVH and DHF in humans. Two clinically relevant approaches to testing this hypothesis are to examine the impact of genetic variations in the natriuretic peptide axis on left ventricular structure and function and to study the effects of acute administration of these peptides. The proposed research has 3 specific aims: (1) to examine the influence of selected polymorphisms in natriuretic peptide genes on plasma natriuretic peptide levels and LVH, using multivariable analyses; (2) to examine the association of genetic variation in natriuretic peptides and natriuretic peptide levels with incident heart failure, using proportional hazards models; (3) to assess the effects of exogenous B-type natriuretic peptide on myocardial function in patients with DHF, using serial hemodynamic and echocardiographic assessments. The first 2 aims will be addressed by studying a large, community-based cohort (Framingham Heart Study) with extensive clinical, echocardiographic, and genetic characterization. Aim 3 will be carried out in the cardiac catheterization laboratory and coronary care unit of a large, referral hospital. The goal of these studies is to elucidate the role of the natriuretic peptides and their genes in ventricular remodeling and diastolic dysfunction, in the hopes of identifying more specific strategies for treating and preventing congestive heart failure. This research and the associated career development activities will provide the candidate with specific training in genetic epidemiology, the hemodynamic and non-invasive assessment of ventricular function, the use of biomarkers, and clinical trials. Each of these skills will be critical to the candidate's long-term goal of becoming an independent clinical investigator with a focus on heart failure.